Small molecules targeting RuvBL complex for triple negative breast cancer

靶向 RuvBL 复合物的小分子治疗三阴性乳腺癌

• 批准号: 10751401
• 负责人: Bingbing Li
• 金额: $ 60.11万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751401
• 关键词: ATP phosphohydrolase; ATR gene; BRCA mutations; Binding; Binding Proteins; Biological; Biological Availability; Breast Cancer Cell; Breast Cancer Model; Cell Line; Cell Survival; Cell physiology; Cells; Complementary DNA; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA lesion; DNA replication fork; Data; Defect; Double Strand Break Repair; Drug Kinetics; Epidermal Growth Factor Receptor; Estrogen Receptors; Evaluation; Excision; Genotoxic Stress; Goals; Government; Human; Ionizing radiation; Lead; Malignant Neoplasms; Molecular; Mus; Mutate; Nonhomologous DNA End Joining; Normal Cell; Oncogenes; Pathway interactions; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Poly(ADP-ribose) Polymerase Inhibitor; Pre-Clinical Model; Process; Progesterone Receptors; Prognosis; Property; Proteins; Publishing; Reactive Oxygen Species; Research; Resistance; Site; Structure; Subgroup; TP53 gene; Therapeutic; Therapeutic Agents; Toxic effect; Xenograft procedure; ataxia telangiectasia mutated protein; brca gene; cancer subtypes; chemoproteomics; course development; druggable target; genome integrity; homologous recombination; improved; in vitro activity; in vivo; inhibitor; lead optimization; malignant breast neoplasm; new therapeutic target; novel; novel lead compound; novel therapeutics; overexpression; p53-binding protein 1; patient derived xenograft model; protein complex; repaired; replication stress; resistance mechanism; response; small molecule; small molecule inhibitor; triple-negative invasive breast carcinoma; tumor

Abstract The goal of this project is to develop small molecule modulators of RuvBL1/L2 complex as potential therapies for triple negative breast cancer (TNBC) by targeting DNA double-strand breaks (DSB) repair pathways. TNBC is a subgroup of breast cancer and is molecularly characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) or HER2 (human epidermal growth factor receptor 2) amplification. DNA replication stress and reactive oxygen species are prevalent in TNBC cells due to activation of various oncogenes. Thus, TNBC cells constantly generate DSBs. In order for the TNBC cells to survive, these lethal DSBs must be repaired. Accordingly, over the course of development of cancer, TNBC cells have co-evolved efficient DSB repair mechanisms that protect them from the endogenous lethal DSBs. Therefore, targeting DNA repair pathways has been proposed as a potentially powerful strategy to develop novel therapeutics for TNBC. By exploiting this unique feature of endogenous DSBs prevalent only in TNBC cells, such therapeutics can offer selective toxicity to TNBC cells without harming normal cells. We recently identified a novel small molecule lead compound to target RuvBL1/L2 to inhibit DSB repair in TNBC cells. In this application, we propose to further develop this small molecule lead compound for the treatment of TNBC with 3 specific aims. In aim 1, we will study the mechanism of action of this novel lead compound. In aim 2, we will optimize this lead compound using different medicinal chemistry strategies. In aim 3, we will investigate the optimized compounds' anti-TNBC efficacy in different preclinical models alone and in combination with PARP inhibitors.

抽象的 该项目的目的是开发Ruvbl1/L2复合物的小分子调节剂作为潜在疗法 用于针对DNA双链断裂（DSB）修复途径的三重阴性乳腺癌（TNBC）。 TNBC 是乳腺癌的亚组，其特征是缺乏雌激素受体的表达 （ER），孕酮受体（PR）或HER2（人表皮生长因子受体2）扩增。脱氧核糖核酸 由于各种激活 癌基因。因此，TNBC细胞不断生成DSB。为了使TNBC细胞生存，这些致命 必须修复DSB。因此，在癌症发展过程中，TNBC细胞已共同发展 有效的DSB修复机制可保护它们免受内源性致命DSB的影响。因此，定位 DNA修复途径已被提议作为一种潜在的有力策略，以开发新的治疗剂 TNBC。通过利用仅在TNBC细胞中普遍存在的内源性DSB的独特特征，此类治疗方法 可以在不损害正常细胞的情况下对TNBC细胞提供选择性毒性。我们最近确定了一个小说 分子将化合物靶向Ruvbl1/L2，以抑制TNBC细胞中DSB修复。在此应用程序中，我们 提议进一步开发这种小分子铅化合物，用于以3个特定目的治疗TNBC。 在AIM 1中，我们将研究这种新型铅化合物的作用机理。在AIM 2中，我们将优化这一点 使用不同的药物化学策略的铅化合物。在AIM 3中，我们将调查优化的 仅在不同的临床前模型中，并与PARP抑制剂结合使用化合物的抗TNBC疗效。